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PubMed2000

Defective remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome.

Cardiolipin (CL) and phosphatidylglycerol (PG) are the major polyglycerophospholipids observed in mammalian tissues. CL is exclusively found in the inner mitochondrial membrane and is required for optimal function of many of the respiratory and ATP-synthesizing enzymes. The role of CL in oxidative phosphorylation is, however, not fully understood and although reduced CL content leads to aberrant cell function, no human disorders with a primary defect in cardiolipin metabolism have been described. In this paper we present evidence that patients with the rare disorder X-linked cardioskeletal myopathy and neutropenia (Barth syndrome, MIM 302060) have a primary defect in CL and PG remodeling. We investigated phospholipid metabolism in cultured skin fibroblasts of patients and show that the biosynthesis rate of PG and CL is normal but that the CL pool size is 75% reduced, indicating accelerated degradation. Moreover, the incorporation of linoleic acid, which is the characteristic acyl side chain found in mammalian CL, into both PG and CL is significantly reduced, whereas the incorporation of other fatty acids into these phospholipids is normal. We show that this defect was only observed in Barth syndrome patients' cells and not in cells obtained from patients with primary defects in the respiratory chain, demonstrating that the observed defect is not secondary to respiratory chain dysfunction. These results imply that the G4.5 gene product, which is mutated in Barth syndrome patients, is specifically involved in the remodeling of PG and CL and for the first time identify an essential factor in this important cellular process.

Cardiolipins↗
PubMed2004

Initiation of apoptotic signal by the peroxidation of cardiolipin of mitochondria.

Overexpression of phospholipid hydroperoxide glutathione peroxidase (PHGPx) in mitochondria of RBL2H3 cells (M15 cells) prevented the release of cytochrome c (cyt.c), the activation of caspase-3, and apoptosis caused by 2-deoxyglucose (2DG), whereas cells overexpressing nonmitochondrial PHGPx(L9) and control (S1) cells were induced to apoptosis. Hydro-peroxide levels in mitochondria of L9 and S1 cells were significantly enhanced by 2DG-induced apoptosis. In contrast, generation of hydroperoxide in mitochondria was protected in M15 cells, which also showed resistance to apoptosis by etoposide, staurosporine, UV irradiation, cycloheximide, and actinomycin D, stimuli that induce apoptosis by the liberation of cyt.c from mitochondria. Cyt.c preferentially binds to the monolayer of cardiolipin (CL), the specific phospholipid of the inner membrane of mitochondria. The amount of cyt.c bound to the monolayer of cardiolipin hydroperoxide (CL-OOH) was much lower than that bound to CL. Cyt.c bound to liposome containing CL was released by peroxidation with a radical initiator. Adenine nucleotide translocator (ANT), which regulates the opening and closing the permeability transition (PT) pore, potentially was inactivated in apoptosis-induced S1 cells 4 h after the addition of 2DG, coincidentally with cyt.c release from mitochondria. ANT activity was suppressed by the fusion of isolated mitochondria with liposomes containing CL-OOH. ANT activity was expressed in proteoliposomes containing 10% CL, but it was competitively inhibited by the addition of CL-OOH. This study suggests that CL peroxidation might have an initiating role in the liberation of cyt.c from the inner membrane, and in the opening of the PT pore via inactivation of ANT. Mitochondrial PHGPx might play a role as an anti-apoptotic factor by protecting CL and reducing CL-OOH.

Adenine Nucleotide Translocator 1↗
PubMed1986

Antitumor and toxicity evaluation of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes.

The antitumor activity of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes was evaluated in P388 ascitic leukemia, disseminated Gross leukemia, and advanced mammary carcinoma. In P388 leukemia, free drug and drug entrapped in liposomes demonstrated equivalent antitumor activity at doses of 2.2 and 4.4 mg/kg, demonstrating 52% and 69% ILS (increase in life-span), respectively. Free doxorubicin at a dose of 10 mg/kg was superior, producing a 185% ILS against 82% with liposomal doxorubicin. With an increase in administered dose the antitumor response with liposomal doxorubicin was much more pronounced; at doses of 20 and 25 mg/kg the ILS was in excess of 376%, with five of ten mice surviving tumor-free. In Gross leukemia, the optimum dose of free doxorubicin, 10 mg/kg, brought about 186% T/C (median survival in treated mice over that in controls, X 100), whereas with liposomal doxorubicin the optimum dose was 16.9 mg/kg, which yielded 214% T/C. In advanced mammary carcinoma, the maximum tumor regression with free doxorubicin was at a dose of 7.5 mg/kg, with two of six mice dying of toxicity. Liposomal doxorubicin caused maximum tumor regression at 10.8 mg/kg dose with no toxic deaths. Doxorubicin entrapped in cardiolipin liposomes was much less toxic than free drug at high doses in normal mice.

AKR murine leukemia virus↗
PubMed1986

Comparative immunotoxicity of free doxorubicin and doxorubicin encapsulated in cardiolipin liposomes.

The immunologic and pharmacologic effects of free doxorubicin and of doxorubicin entrapped in liposomes were compared in mice at a dose of 20 mg/kg. Liposomes for encapsulation of doxorubicin were prepared by using 39.35 mumol drug, 19.65 mumol cardiolipin, 100 mumol phosphatidylcholine, 68.4 mumol cholesterol, and 38.9 mumol stearylamine. Pharmacologic disposition studies after a dose of 20 mg/kg demonstrated 7- to 10-fold higher drug concentrations in the spleen at all time points following administration of doxorubicin entrapped in cardiolipin liposomes than after the free drug. The levels in liver were 4- to 5-fold higher with liposomal drug, whereas the cardiac uptake with liposomal doxorubicin was significantly lower than with free drug. Mice were sacrificed on days 1, 8, 15, and 22 after drug administration and spleen cells were isolated for studies of sensitization to alloantigens for cell-mediated cytolysis and of proliferation in response to mitogens. Mice treated with free doxorubicin demonstrated a decrease of more than 50 fold (compared with saline control) in allospecific cytotoxic activity on day 15; normal levels were recovered by day 22. The animals treated with doxorubicin encapsulated in liposomes showed a similar but not more pronounced fall to low levels. The total lytic activity per spleen after free drug or drug encapsulated in liposomes was markedly reduced at day 8, but this activity was fully recovered by day 15 in animals receiving liposomal doxorubicin; in those receiving free drug it had not recovered fully even at day 22. The proliferative response to concanavalin A was affected by the two forms of doxorubicin in a pattern very similar to the cytotoxic response. The proliferative response to lipopolysaccharide was markedly depressed by doxorubicin delivered in either form, and the kinetics were not altered by the mode of administration. The concentration of doxorubicin in spleen was markedly increased with liposomal delivery, but did not result in greater toxicity than that of free drug according to the immunologic parameters evaluated.

Animals↗
PubMed1988

Splenic and renal infarction in systemic lupus erythematosus: association with anti-cardiolipin antibodies.

A 37-year-old female, known to have systemic lupus erythematosus (SLE) and markedly raised anti-cardiolipin antibody levels in association with the lupus anticoagulant, presented with a symptomatic segmental splenic infarction. There was a past history of cerebral infarction. Abdominal computed tomography (CT) demonstrated the area of splenic infarction, and an asymptomatic right renal infarct. This patient illustrates the unusual occurrence of multiple visceral infarcts, in association with anti-cardiolipin antibodies, complicating SLE.

Adult↗
PubMed1975

Rate of restoration of cardiolipin and other major phospholipids during liver regeneration in rat.

The rate of restoration of liver phospholipids, especially cardiolipin, during liver regeneration after two-thirds partial hepatectomy, was studied. Preoperative content of cardiolipin was not restored during the first week of regeneration, while this was the case for the other major liver phospholipids. The observations are discussed in relation to the morphogenesis of mitochondria during liver regeneration.

Animals↗
PubMed2004

[A cerebral watershed infarction after general anaesthesia in a patient with increased anti-cardiolipin antibody level].

During the first generalised epileptic attack, a patient suffered a humerus fracture which necessitated an operation. This patient also had a history of spontaneous lung emboli and an elevated anti-cardiolipin plasma level for which coumarin was prescribed but was stopped preoperatively. After induction of general anaesthesia for a total shoulder arthroplasty, the patient became hypotensive and the bispectral index recorded perioperatively dropped to 0. Postoperatively, the patient developed signs of a unilateral borderzone cerebral infarct in the area of the medial cerebral artery. The possible pathomechanisms involved are discussed. In cases of known cerebral pathology intraoperative hypotension should be avoided by at all costs. Patients with increased anti-cardiolipin antibody levels and who suffer from epileptic attacks have an increased risk of thromboembolic events.

Anesthesia, General↗
PubMed2002

Presence of two novel cardiolipins in the halophilic archaeal community in the crystallizer brines from the salterns of Margherita di Savoia (Italy) and Eilat (Israel).

Two novel cardiolipin derivatives were recently detected in Halobacterium salinarum, namely an archaeal analog of bisphosphatidylglycerol (BPG) and a glycocardiolipin (GlyC). GlyC was found to be tightly bound to bacteriorhodopsin. To obtain information on the presence and distribution of these archaeal cardiolipins, we have analyzed the lipids extracted from the crystallizer ponds of the salterns of Margherita di Savoia (Italy) and Eilat (Israel) and from cultures of representative species of the Halobacteriaceae by electrospray ionization mass spectrometry. BPG was present as a minor lipid component in the lipids extracted from the biomass of the Margherita di Savoia and the Eilat salterns, while GlyC was detected only in the extract of the biomass of Margherita di Savoia. Both compounds were enriched in the membrane fraction obtained by dialysis of the cells against distilled water. We detected BPG in all members of the Halobacteriaceae tested, but GlyC has so far been found only in the genera Halobacterium and Haloarcula. A sulfated diglycosyl diether was the major glycolipid detected in the biomass of both salterns.

Biomass↗
PubMed2005

Cardiolipin in energy transducing membranes.

Cardiolipin is a phospholipid located exclusively in energy transducing membranes such as the bacterial cytoplasmic membrane and the inner membrane of mitochondria. It plays both a structural and a functional role in many multimeric complexes associated with these membranes. The role of cardiolipin in higher order organization of components of the mitochondrial respiratory chain revealed by a combined molecular genetic and biochemical approach is described.

Animals↗
PubMed2004

A short, concise route to diphosphatidylglycerol (cardiolipin) and its variants.

A new approach is described for the synthesis of the cardiolipin family of phospholipids that uses phosphonium salt methodology. The method involves the reaction of 2-O-protected glycerol with a trialkyl phosphite derived from 1,2-diacylsn-glycerol in the presence of pyridinium bromide perbromide and triethylamine to afford the phosphoric triesters. The synthesis involves three steps and allows the preparation of a wide range of cardiolipins with different substitution patterns and chain lengths, including unsaturated derivatives. The use of inexpensive protecting groups and the ease of purification facilitate this synthetic route and allow its scale-up in a higher overall yield (72%) than the literature methods.

Cardiolipins↗
PubMed1990

Antiphospholipid antibodies and recurrent pregnancy loss: correlation between the activated partial thromboplastin time and antibodies against phosphatidylserine and cardiolipin.

Concordance was determined among the presence of the lupus anticoagulant measured by prolongation of the activated partial thromboplastin time and IgG and IgM antibodies against phosphatidylserine and cardiolipin in 47 patients selected for study because of histories of recurrent spontaneous pregnancy loss and a positive test for at least one antiphospholipid antibody. Forty-five of 47 patients (96%) had a prolonged activated partial thromboplastin time, ranging from 46 to 150 seconds. Elevated levels of IgG antiphosphatidylserine antibodies and IgM antiphosphatidylserine antibodies were present in 41 (87%) and in 19 (40%) of samples, respectively. Antibodies against cardiolipin were less commonly observed; IgG anticardiolipin antibodies in only 32 (68%) of 47 samples and IgM anticardiolipin antibodies in 15 (36%) of 42 samples. Neither the level of IgG antiphosphatidylserine antibodies nor the level of IgG anticardiolipin antibodies correlated well with the degree of prolongation of coagulation in the activated partial thromboplastin time (R = 0.312, p = 0.032 for IgG antiphosphatidylserine antibodies versus activated partial thromboplastin time; R = 0.251, p = 0.088 for IgG anticardiolipin antibodies versus activated partial thromboplastin time). Concordance with the activated partial thromboplastin time, however, was observed in 41 (87%) samples for IgG antiphosphatidylserine antibodies and in only 32 (68%) samples for IgG anticardiolipin antibodies. Our conclusion is that the antiphosphatidylserine assay correlates best, although not totally, with the presence of lupus anticoagulant and that the antiphosphatidylserine assay is more sensitive than testing for anticardiolipin.

Abortion, Habitual↗
PubMed1978

Polymorphic phase behaviour of cardiolipin as detected by 31P NMR and freeze-fracture techniques. Effects of calcium, dibucaine and chlorpromazine.

1. The influence of Ca2+ on the polymorphic phase behaviour of cardiolipin has been investigated employing 31P NMR and freeze-fracture techniques. The close correlation between the results obtained here and previous X-ray studies (Rand, R.P. and Sengupta, S. (1972) Biochim. Biophys. Acta 255, 484--492) confirms 31P NMR as a useful analytical procedure for investigating the polymorphic phase behaviour of hydrated phospholipids. 2. Ca2+ induces formation of the hexagonal (H11) phase via an intermediary phase which is observed at Ca2+/cardiolipin ratios of less than 1 (mol/mol). This intermediary appears to consist of "inverted' structure which lies adjacent to regions of bilayer structure. 3. The local anaesthetics dibucaine and chlorpromazine produce similar phase changes for cardiolipin as does Ca2+. It is suggested that the anaesthetics interact with the membrane in their charged form and induce their effects by charge neutralization.

Calcium↗
PubMed1986

Interaction of 5-iminodaunorubicin with Fe(III) and with cardiolipin-containing vesicles.

5-Iminodaunorubicin is an anthracycline derivative exhibiting promising antitumor activity. Using potentiometric and spectroscopic measurements we have shown that 5-iminodaunorubicin forms with Fe(III) a complex in which three molecules of drug are bound to one Fe(III) ion. Each molecule is chelated through the C-12-carbonyl and the C-11-phenolate oxygen atoms. The stability constant is 1.6 X 10(34). Using circular dichroism measurements we have studied the interactions of 5-iminodaunorubicin with cardiolipin-containing vesicles. We have shown that cardiolipin could bind one molecule of drug without penetration of the dihydroanthraquinone moiety into the bilayer.

Cardiolipins↗
PubMed1986

Interaction of adriamycin with cardiolipin-containing vesicles. Evidence of an embedded site for the dihydroanthraquinone moiety.

In the presence of cardiolipin-containing small unilamellar vesicles, the antitumor compound adriamycin loses its ability to catalyse the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase. The data strongly suggest that in the presence of cardiolipin the dihydroanthraquinone moiety is embedded in the phospholipid bilayer and thus inaccessible to the enzyme.

Anthraquinones↗
PubMed1987

Melittin induces HII phase formation in cardiolipin model membranes.

The interaction of melittin with bovine heart cardiolipin model membranes was investigated via binding assays, 31P-NMR, freeze-fracture electron microscopy, small angle X-ray diffraction and fluorescence based fusion assays. A strong binding (Kd less than 10(-7) M) appeared to be accompanied by the formation of large structures, resulting from a fusion process of extremely fast initial rate. As the melittin content is increased, bilayer structure is gradually lost and from a cardiolipin to melittin ratio of about 6 the lipid starts to organize itself in an hexagonal HII phase. At lower temperatures (T less than 40 degrees C) the coexistence of another structure is observed, characterized by a broad isotropic 31P-NMR signal and giving rise to sharp X-ray reflections, most probably a cubic phase, as suggested also be freeze-fracture images, showing orderly stacked particles. The results are discussed in relation to contrasting observations on the structural changes induced by melittin in the zwitterionic phospholipid system of dipalmitoylphosphatidylcholine (Dufourcq. J. et al. (1986) Biochim. Biophys. Acta 859, 33-48). The biological relevance of the observations with respect to the process of protein insertion into membranes is indicated.

Animals↗
PubMed1994

Significant stabilization of the phosphatidylcholine bilayer structure by incorporation of small amounts of cardiolipin.

The effects of the negatively charged phospholipid cardiolipin on the structural properties of egg-yolk phosphatidylcholine (EyPC) liposomal membranes were studied by monitoring the water permeability of the liposomes caused by osmotic shrinkage in hypertonic glucose solution. Incorporation of small amounts of bovine heart cardiolipin (BhCL) into the EyPC membranes caused a significant decrease in their water permeability associated with stabilization of the membrane structure. Much evidence obtained by attenuated total reflection IR spectroscopy suggested that incorporation of BhCL into the EyPC membranes causes a cooperative conformational change in the EyPC polar head groups, but does not alter the fluidity of the bilayer structure in the fluid liquid crystalline state. Incorporation of small amounts of BhCL stabilized the intermolecular hydrogen-bonded network including water molecules of the hydration layers at the bilayer surface that are important for the stable bilayer configuration of the EyPC molecules. The antisymmetric PO2- frequencies of the EyPC membrane with incorporated BhCL suggested that the BhCL content of 50 mol% induced a change in the phase behaviors of mixed BhCL/EyPC membranes.

Animals↗